Pamela Kidd

Subcutaneous granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome: toxicity, pharmacokinetics, and hematological effects.

The toxicity, pharmacokinetics, and hematologic effects of granulocyte-macrophage colony-stimulating (GM-CSF) were studied in a phase I/II trial of 16 patients with myelodysplastic syndrome (MDS). The GM-CSF was administered subcutaneously (SC) daily so as to achieve prolonged blood levels and to establish an outpatient treatment regimen. Four dose levels were administered for ten days: 0.3 microgram/kg/d (three patients), 1.0 microgram/kg/d (three), 3.0 micrograms/kg/d (four), and 10.0 micrograms/kg/d (six). The most common toxicities were fever and a flu-like syndrome, which were dose-dependent. The maximum-tolerated dose was 10.0 micrograms/kg/d, which induced severe rigors (two patients), fever greater than 40 degrees C (one), severe bronchospasm (one), and WBC 60,000 (one). In one patient, refractory anemia with excess blasts in transformation (RAEB-T) progressed to acute nonlymphocytic leukemia after two doses of GM-CSF, and the patient died of leukemia that did not respond to chemotherapy. After doses of 3.0 and 10.0 micrograms/kg, serum GM-CSF levels peaked at 3.8 to 6.3 hours, and persisted for 14 and 24 hours, respectively. Circulating granulocytes (neutrophils and bands) increased in a dose-dependent manner, as 11 of 13 patients who received greater than or equal to 1.0 microgram/kg/d responded with a two- to 194-fold increase. Although the neutrophils usually returned to pretreatment levels shortly after stopping GM-CSF, two patients continue to exhibit an elevation of neutrophils for 6 months. Dose-related increases in circulating monocytes and eosinophils were also noted. Transient increases in platelet and reticulocyte counts were observed in two and three patients, respectively. Five of the 16 patients later received maintenance GM-CSF at 3 micrograms/kg/d for 2 to 9 weeks. All showed a dramatic increase in neutrophils after 2 weeks. Thereafter, despite continued therapy, the neutrophil count in four patients declined markedly. In conclusion, GM-CSF is well tolerated by the SC route and induces striking, but usually temporary, improvement in the neutropenia of MDS. Larger prospective phase III trials will determine the duration of hematologic responses and the impact on infection, morbidity, and mortality.

A pilot study of low-dose zidovudine in human immunodeficiency virus infection.

BACKGROUND Zidovudine delays the progression of human immunodeficiency virus (HIV) infection but is associated with hematologic toxicity at high doses. Regimens are needed that preserve or enhance efficacy and reduce toxicity. Acyclovir has been reported to potentiate the effect of zidovudine on HIV in vitro. METHODS We conducted a Phase II open-label, dose-escalating trial to evaluate the clinical and antiviral effects of zidovudine at low (300 mg daily, 28 subjects), medium (600 mg, 24 subjects), and high (1500 mg, 15 subjects) doses, either with or without acyclovir (4.8 g) by random assignment. The subjects had the acquired immunodeficiency syndrome (AIDS)-related complex, but not AIDS. All of them had either HIV p24 antigenemia or plasma viremia and CD4-lymphocyte counts of 200 to 500 per cubic millimeter when they began treatment. RESULTS Performance scores and fatigue improved the most in the low- and medium-dose zidovudine groups (both P less than or equal to 0.025). Those assigned to low-dose zidovudine gained the most weight and had the greatest improvement in the mean CD4-lymphocyte count (from 321 per cubic millimeter at base line to 412 per cubic millimeter after 12 weeks, P = 0.01). The proportion of subjects in whom HIV antigenemia resolved, the decrease in the level of antigenemia, and the reduction in the plasma virus titers were similar at all three doses. Subjects assigned to receive the low or medium dose who subsequently crossed over to the 1500-mg dose (n = 19) did not have an increase in CD4-cell counts or a decline in levels of HIV antigen, but they did have dose-related toxicity. The addition of acyclovir to zidovudine was well tolerated, but it did not enhance any of zidovudines antiretroviral effects. CONCLUSIONS In this pilot study a very low dose of zidovudine (300 mg) had clinical and virologic effects similar to those of higher daily doses (600 and 1500 mg). The minimal effective dose of zidovudine for the treatment of HIV infection has yet to be determined, and further studies of very low daily doses are warranted.

Results of the flow cytometry ACTG quality control program: Analysis and findings☆

The AIDS Clinical Trial Groups (ACTG) Immunology Committee was charged with initiating a quality control program for all laboratories participating in the ACTG program reporting flow cytometry data. Forty-one laboratories were evaluated. This report defines the goals of this program and the subsequent findings after 19 send-outs were made. Both HIV positive volunteer donors and normal age-matched donors were used. Sample sets included both heparin and EDTA anticoagulated bloods. Laboratories were asked to report hematologic parameters as well as flow cytometry data both in percentages and absolute numbers. Results were evaluated using nonparametric statistical analysis. Robust CVs and interquartile ranges were used to define the performance of individual laboratories for each CD subset analyzed. Intralaboratory reproducibility was analyzed by paired sample sets. All laboratories were found to be able to define normal samples as normal. Seventy-five percent of the laboratories were able to define abnormal samples as abnormal. Twenty-five percent could not identify two abnormal samples as abnormal. Forty percent of the labs were found unable to reproduce paired samples within an absolute of +/- 5%. EDTA was found slightly superior to heparin in bloods evaluated by flow cytometry within 30 hr of collection. The analysis of specific histograms, questionnaires, and data analysis led to a specific set of recommendations for performance of flow cytometry studies.

Three-color supplement to the NIAID DAIDS guideline for flow cytometric immunophenotyping.

Since the publication of the ‘‘NIAID DAIDS Guideline for Flow Cytometric Immunophenotyping’’ (1) in 1993, significant scientific and technological advances in the development and production of reagents, instrumentation, and software have permitted widespread access to multicolor flow cytometry in both research and clinical laboratories. As is often the case with complex new technologies, each advance, while opening up exciting new capabilities, can also bring new sources of variability and a commensurate increase in the requirements for quality assurance at all levels. The purpose of this document is to update the 1993 NIAID DAIDS Guideline with new recommendations designed to help standardize the methodology and minimize measurement variability in determining patients’ CD4 and CD8 T-cell counts using 3-color flow cytometry. Issues pertaining to specimen collection and handling, problematic specimens, hematology, and laboratory performance assessment were addressed in the previous guideline.1 In assembling this supplement, factors such as reduced technician time, decreased need for isotype controls, fewer assay tubes, and the potential for diminished cost were considered advantages of 3-color (vs. 2-color) flow cytometry. In contrast, the increased complexity of factors such as spectral compensation, instrument set up, and data collection/analysis were considered disadvantages. In addition, some antibody combinations are not commercially available, and certain third-color fluorochromes may not be optimal with all flow cytometers. The specifications and recommendations contained herein were developed for use in laboratories that support clinical trials and epidemiologic studies done under the auspices of the National Institute of Allergy and Infectious Diseases, Division of AIDS (NIAID DAIDS). Efforts currently underway by the Centers for Disease Control and Prevention and by the National Committee for Clinical Laboratory Standards (NCCLS) will likely provide additional guidance in this rapidly changing arena. 5.1 3-COLOR IMMUNOPHENOTYPING 5.01. 3-Color Monoclonal Antibody Panel

CD7+ acute non-lymphocytic leukemia: Evidence for an early multipotential progenitor

Nineteen of 71 (26%) cases of acute myelogenous leukemia (AML) were found to express CD7, a cell surface marker found early during T lineage differentiation. These myeloid leukemias often expressed other lymphoid markers and frequently had rearranged T-cell receptor beta and immunoglobulin heavy chain genes. We propose that in CD7+ AML, the malignant transformation occurred in a CD7+ progenitor cell. CD7+ myeloid leukemic precursors may be capable of limited differentiation with loss of CD7 during the initial phase of the disease, but this capacity may diminish during the course of treatment such that CD7 expression persists.

Chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is an illness characterized by extraordinary fatigue, along with subjective cognitive, musculoskeletal, and sleep symptoms. It is a symptom-based diagnosis without distinguishing physical examination findings or routine laboratory findings. Although infectious, immunological, neuroendocrine, sleep disorder, and psychiatric mechanisms have been investigated, a unifying etiology for CFS has yet to emerge. Regardless of the pathogenesis, persons with CFS have substantially impaired functional status, similar to that of other chronic illnesses, resulting in significant personal and economic morbidity. Whether CFS represents a discrete disorder is still unknown. Those individuals who fulfill the criteria of CFS suffer striking functional impairment in their personal and professional relationships. Treatment is largely empiric and rarely curative. Improving upon this outcome requires a better understanding of CFS pathophysiology. Evidence to date points to the importance of biological and psychological contributions. Future study which simultaneously assesses both of these factors may provide the insight needed to unravel these complexities and consequently enhance the care of patients with CFS.

Prediction of CD4 count from CD4 percentage: experience from three laboratories.

OBJECTIVE CD4 counts have been used to monitor progression of disease in HIV infection as criteria for initiation of therapy, and to stratify and follow patients in clinical trials. Recently, the Centers for Disease Control and Prevention (CDC) has made CD4 counts part of the classification of HIV disease. Because a CD4 percentage may be the only laboratory information available, this study was initiated to determine whether the correlation between CD4 percentages and CD4 counts is sufficiently high to enable these measures to be substituted for each other. DESIGN, SETTING AND PATIENTS One thousand consecutive CD4 measurements from the University of Washington (UW) were used to create a model that was tested using datasets of 1000 CD4 measurements each from Maryland Medical Laboratories (MML) and Rush-Presbyterian-St Lukes Medical Center (Rush). The patients were not selected for age, sex, risk group or treatment. All patients from MML and Rush were known to be HIV-positive, while the HIV status of all UW patients was unknown. RESULTS The model predicted that a patient with a CD4 percentage > or = 14% would have a CD4 count > or = 200 x 10(6)/l(if CD4 percentage of 14% was used, 9% of patients would have a CD4 count > or = 200 x 10(6)/l), and a patient with a CD4 percentage > or = 27% would have a CD4 count > or = 500 x 10(6)/l(if CD4 percentage of 27% was used, 17% of patients would have a CD4 count > or = 500 x 10(6)/l). CONCLUSIONS These CD4 percentage correlations may be useful when a white blood cell and lymphocyte count are not available to calculate the CD4 count.

Idiopathic myelofibrosis in blast transformation with 4;12 and 5;12 translocations and a 7q deletion

A case of a patient who developed a leukemic transformation following an 8.5-year history of idiopathic myelofibrosis (IMF) with myeloid metaplasia is presented. Surface marker analysis identified the blast cells as myeloid in lineage. The karyotype of unstimulated peripheral blood cells was 46,XY,t(4;12)(q26;15),t(5;12)(q13;q24),del(7)(q22). In the literature, the 7q- has a minor association with IMF, and the t(5;12) translocation has been reported in one case of acute nonlymphocytic leukemia, but neither the t(4;12) nor the combination of these three abnormalities has been reported in IMF.

Myasthenia Gravis and Lymphoblastic Lymphoma Antiacetylcholine Receptor Antibody as a Tumor Marker-A Case Report

This report documents an association between lymphoblastic lymphoma and myasthenia gravis. Elevation of acetylcholine receptor antibody titer was an unusual marker for the lymphoblastic lymphoma. Following chemotherapy all symptoms of myasthenia gravis resolved and the acetylcholine receptor antibody titer normalized. The patient remains in complete remission off all therapy 20 months since the diagnosis of myasthenia gravis was made and 12 months after chemotherapy for her lymphoma.

Intussusception in an infant with acute lymphoblastic leukemia : A case report and review of the literature

Purpose: An ileocccal intussusception developed in a 7-month-old infant with acute lymphoblastic leukemia (ALL) during induction therapy. Gastrointestinal complications, especially intussusception, are rare in children with ALL. Patient and Methods: The history of a 7-month-old white boy with ALL in whom an ileocecal intussusception developed 1 week into induction chemotherapy was reviewed. In addition, a literature search was performed to determine the prevalence of this complication in children with acute leukemia. Results: On day 4 of induction chemotherapy for B-lineage ALL. the infant developed abdominal distension with hypoactive bowel sounds. After a barium enema and abdominal computed tomography scan, the symptoms were determined to be caused by an ileocecal intussusception. Chemotherapy was resumed I week after immediate surgical intervention (reduction of intussusception and resection of the “leading edge”) with an uneventful postoperative recovery. Histopathologic examination of the resected edge revealed an intact mucosa with areas of necrosis in the sub-mucosa. This was associated with a dense lymphoid infiltrate composed of mature lymphocytes and leukemie cells, edema, and focal necrosis. Despite a 1-week delay in chemotherapy, a complete remission was documented at day 32. Discussion: The prevalence of intussusception in children with ALL and its possible etiology are discussed. The pathologic changes, clinical manifestations, and treatment outcome are briefly mentioned.